Dose–exposure–IGF-I response of once-weekly somapacitan in adults with GH deficiency

Objective Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose–responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose–insulin-like growth factor I (IGF-I) responses in AGHD patients. Design Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials. Methods Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose–IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing. Results The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7–9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3–4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose–exposure–IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment. Conclusions This study extends the knowledge of the somapacitan dose–IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

oestrogen use and age on k in , and body weight, sex, race (Asian non-Japanese) and age on E max .
All covariate values used in the models were baseline values. For  were pooled with the largest group (White) in the covariate analyses.

Evaluation of somapacitan and somatropin models
The final PK and PK/PD models were qualified by evaluation of the precision of fixed effect parameters, the shrinkage of random effects and the goodness-of-fit by visual inspection of model diagnostics plots, including prediction-corrected visual predictive checks (VPCs).
VPCs are shown in Supplementary Fig. 1 for the somapacitan PK model ( Supplementary   Fig. 1A), the somapacitan PK/PD model (Supplementary Fig. 1B) and the somatropin PK/PD model (Supplementary Fig. 1C). The models reproduced the overall trends of the phase 3 data, including the median and variability. Hence, the models provided accurate prediction of the observed data.
Sensitivity analyses showed similar results when dividing age groups at 60 years (>60, ≤60) and 65 years (>65, ≤65) in the PK and PK/PD models. Different age groups were used for starting dose groups (>60, ≤60) and for covariate age groups in the modelling analysis (>65, ≤65), due to a discrepancy between current clinical treatment guidelines (2) and the definition of geriatric populations in regulatory guidelines (3).

Dose-exposure-IGF-I estimation based on final somapacitan PK and PK/PD models
Estimates for the individual dose-exposure-IGF-I-response pairs at maintenance dose levels after titration were constructed based on individual estimates for PK and PK/PD parameters from the final PK and PK/PD models. Fixed dose levels were defined as the median of doses registered for an individual after the last titration visit. Average exposure (C avg ) and average IGF-I response (IGF-I avg ) were estimated from the area under the curve (AUC) of individual predicted profiles during maintenance treatment for the fixed dose level. No imputation was performed for subjects not completing titration (n = 6).
The individual dose-exposure-IGF-I-response curves across the somapacitan dose range of 0.1-8 mg were estimated from the AUC of individual predicted profiles using the final PK and PK/PD models.

Somatropin PK/PD analysis methods
The somatropin PK/PD model was based on data from three phase 3 trials in patients with adult growth hormone deficiency (AGHD) (Tables 1 and 2) (4-6). The PK of somatropin was described by a one-compartment model with linear absorption and clearance, while somatropin PK/PD was described using an indirect response model with additive E max effect relationship between PK and IGF-I, like the PK/PD model for somapacitan. Somatropin model development and dose-response analyses were performed similarly to the procedures described for somapacitan.    c Two subjects titrated up or down but returned to starting dose level.